Under normal conditions, basal levels of wild-type p53 promote mitochondrial function through multiple mechanisms. Remarkably, some missense mutations of p53, in contrast to the null state, can result in the retention of its metabolic activities. These effects are particularly prominent in the mitochondria and demonstrate a functional role for mutant p53 in cancer metabolism. This review summarizes accumulating data on the mechanisms by which p53 missense mutations can regulate mitochondrial metabolism and promote the viability and survival of both normal and cancer cells, thus acting as a double edged sword for the host. Greater understanding of these mechanisms may provide insights for developing new treatment or preventive strategies against cancer.

Edited by Linda SpremulliAlthough exercise is linked with improved health, the specific molecular mechanisms underlying its various benefits require further clarification. Here we report that exercise increases the nuclear localization and activity of p53 by acutely down-regulating coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4), a carrier protein that mediates p53 import into the mitochondria. This response to exercise is lost in transgenic mice with constitutive expression of CHCHD4. Mechanistically, exerciseinduced nuclear transcription factor FOXO3 binds to the CHCHD4 promoter and represses its expression, preventing the translocation of p53 to the mitochondria and thereby increasing p53 nuclear localization. The synergistic increase in nuclear p53 and FOXO3 by exercise can facilitate their known interaction in transactivating Sirtuin 1 (SIRT1), a NAD ؉ -dependent histone deacetylase that mediates adaptation to various stresses. Thus, our results reveal one mechanism by which exercise could be involved in preventing cancer and potentially other diseases associated with aging.The nuclear transcriptional activities of p53, well established to play a critical role in tumor suppression, are dynamically regulated by multiple factors, including posttranslational modifications and protein-protein interactions (1-3). Accumulating evidence also shows that p53 localization in non-nuclear subcellular compartments, such as the cytosol and mitochondria, can regulate cellular processes like autophagy and metabolism (4 -6). Although stress-mediated p53 translocation to the mitochondria and its role in cell death have been well delineated, the effect of p53 translocation into mitochondria under normal states is less clear (7,8). Thus, understanding the regulation of p53 partitioning into the mitochondria under physiologic conditions may provide new insights into its tumor-suppressive functions.We reported previously that CHCHD4, 2 the mammalian homolog of the yeast mitochondrial disulfide relay system carrier Mia40, interacts with p53 and mediates its translocation into mitochondria (9). Unlike other mechanisms by which proteins can be imported into mitochondria, the disulfide relay system is coupled to respiration, perhaps reflecting a homeostatic mechanism by which the import of p53 can be regulated by mitochondrial activity (10, 11). Subsequently, p53 import into mitochondria by CHCHD4 facilitates the repair of oxidative mtDNA damage, complementing the nuclear role of p53 in regulating mitochondrial respiration (9, 12, 13). However, these observations also raise questions regarding the physiological significance of the partitioning of p53 between the nucleus and mitochondria and whether such a mechanism can be demonstrated in vivo under normal conditions.Exercise elicits many complex physiological responses, including the induction of specific transcription factors such as PGC-1␣ and peroxisome proliferator-activated receptors, which transactivate mitochondrial biogenesis genes (14, 15). As a mitochondrial protein ...

During fetal development, the uterine environment can have effects on offspring bone architecture and integrity that persist into adulthood; however, the biochemical and molecular mechanisms remain unknown. Myostatin is a negative regulator of muscle mass. Parental myostatin deficiency (Mstn tm1Sjl/+ ) increases muscle mass in wild-type offspring, suggesting an intrauterine programming effect. Here, we hypothesized that Mstn tm1Sjl/+ dams would also confer increased bone strength. In wild-type offspring, maternal myostatin deficiency altered fetal growth and calvarial collagen content of newborn mice and conferred a lasting impact on bone geometry and biomechanical integrity of offspring at 4 mo of age, the age of peak bone mass. Second, we sought to apply maternal myostatin deficiency to a mouse model with osteogenesis imperfecta (Col1a2 oim ), a heritable connective tissue disorder caused by abnormalities in the structure and/or synthesis of type I collagen. Femora of male Col1a2 oim/+ offspring from natural mating of Mstn tm1Sjl/+ dams to Col1a2 oim/+ sires had a 15% increase in torsional ultimate strength, a 29% increase in tensile strength, and a 24% increase in energy to failure compared with age, sex, and genotype-matched offspring from natural mating of Col1a2 oim/+ dams to Col1a2 oim/+ sires. Finally, increased bone biomechanical strength of Col1a2 oim/+ offspring that had been transferred into Mstn tm1Sjl/+ dams as blastocysts demonstrated that the effects of maternal myostatin deficiency were conferred by the postimplantation environment. Thus, targeting the gestational environment, and specifically prenatal myostatin pathways, provides a potential therapeutic window and an approach for treating osteogenesis imperfecta.osteogenesis imperfecta | developmental origins of health and disease | fetal programming | myostatin | bone health O steogenesis imperfecta (OI) is a genetically and clinically heterogeneous heritable connective tissue disorder characterized by anomalies in type I collagen-containing tissues, particularly bone. Clinical manifestations include osteopenia/osteoporosis, fractures, skeletal deformities, short stature, and skeletal muscle weakness. Current therapies entail use of antiresorptive drugs and surgical interventions but have limited success (1). New approaches that decrease fracture risk while minimizing long-term damage to bone integrity are greatly needed. Myostatin, or growth and differentiation factor 8 (GDF8), is a TGF-β family member and negative regulator of muscle growth and development. It is highly conserved across species, primarily expressed in muscle cells, and participates in paracrine and endocrine signaling (2). Recently, we and others have shown that inhibiting myostatin, either genetically or pharmacologically, increases muscle mass and improves bone microarchitecture (3) and mechanical strength (4) in the OI murine (Col1a2 oim ) model. In addition to regulating muscle growth postnatally, myostatin deficiency in the maternal environment increases muscle mass in ...

26Direct-acting antiviral use is associated with increased survival in hepatitis C-related 27 hepatocellular carcinoma patients. Patients treated with direct-acting antiviral who achieved 28 hepatitis C cure had additionally increased survival versus those treated with direct-acting 29 antiviral who did not achieve hepatitis C cure. This study supports the use of direct-acting 30 antiviral for hepatitis C treatment in hepatocellular carcinoma patients. Abbreviations 53 DAA: Direct-acting antivirals; SVR12: 12-week sustained virologic response; HCC: 54 hepatocellular carcinoma; HCV: hepatitis c virus; OS: median overall survival; AJCC: American 55 Joint Committee on Cancer stage; MELD: Model for end stage liver disease; HR: hazard ratio 4 56 Abstract: 57 Background: To investigate the impact of direct-acting antivirals (DAA) and 12-week sustained 58 viral response (SVR12) in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C 59 virus (HCV) infection. Methods: Retrospective analysis of HCC patients diagnosed from 2005 60 to 2016 at an urban tertiary-care hospital. Kaplan-Meier curves and multivariable Cox 61 proportional hazards models were used to assess survival. Results: 969 patients met inclusion 62 criteria. 478 patients received interventional oncology treatment (catheter-based therapies, 63 ablation or combination locoregional therapies), 141 received supportive care (palliative or no 64 treatment), 125 underwent liver transplantation, 112 had tumor resection and 94 received 65 chemotherapy or radiation as their primary treatment. Median overall survival of the cohort was 66 24.2 months (95% CI: 20.9-27.9). 470 patients had HCV (56%). 123 patients received DAA 67 therapies for HCV (26.2%), 83 of whom achieved SVR12 (68%). HCV-positive and HCV-68 negative patients had similar survival (20.7 months vs 17.4 months, p=0.22). Patients receiving 69 DAA therapy had an overall survival of 71.8 months (CI: 39.5-not reached) vs 11.6 months (CI: 70 9.8-14.5) for patients without DAA therapy (p<0.0001). DAA patients who achieved SVR12 had 71 an overall survival of 75.6 months (CI: 49.2-not reached) vs the non-SVR12 group (26.7 months, 72 CI: 13.7-31.1, p<0.0001). Multivariable analysis revealed AJCC, Child-Pugh Score, MELD, 73 tumor size, tumor location and treatment type had independent influence on survival (p<0.05). 74 In HCV-positive patients, AJCC, MELD, tumor location, treatment allocation and DAA were 75 significant (p<0.05). In patients receiving DAA therapy, only MELD and SVR12 were predictive 76 of overall survival (p<0.05). Conclusions: DAA therapy and achieving SVR12 is associated 77 with increased overall survival in HCV patients with HCC. 78 5 79